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PubMed2005

Prognostic effect of insertion/deletion polymorphism of the ace gene on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes.

OBJECTIVE: The insertion/deletion (I/D) polymorphism of the ACE gene has been reported to be associated with diabetic microvascular or macrovascular complications. The aim of the present study was to investigate the prognostic effect of I/D polymorphism on renal and cardiovascular clinical outcomes in Chinese patients with type 2 diabetes. RESEARCH DESIGN AND METHODS: A consecutive cohort of 1,281 Chinese patients with type 2 diabetes were followed for 41.3 +/- 21.6 months. Renal end points were defined as renal death and events (need for dialysis, plasma creatinine >/=500 micromol/l, or doubling of plasma creatinine of baseline value >/=150 micromol/l). Cardiovascular end points were defined as cardiovascular death and events, which included ischemic heart disease, heart failure, cerebrovascular accident, and revascularization requiring hospital admission. The I/D polymorphism of the ACE gene was examined by PCR followed by agarose gel electrophoresis. RESULTS: The frequencies of ACE gene I/D polymorphisms were in Hardy-Weinberg equilibrium. Patients who developed a renal end point (n = 98) had higher frequencies of DD genotype (19.4 vs. 10.8%, P = 0.018) and D allele (41.3 vs. 31.8%, P = 0.006) compared with subjects who did not (n = 1,183). The cumulative rates of renal end points were 10.0, 19.2, and 24.4% in the II (n = 595), DI (n = 539), and DD genotype carriers (n = 147), respectively (log rank P = 0.004). In multiple Cox regression analysis, the occurrence of renal end points remained significantly influenced by I/D polymorphism with a dominant deleterious effect of the DD genotype (DD versus II, adjusted hazard ratio 2.80 [95% CI 1.49-5.29]). There was no prognostic effect of I/D polymorphism on cardiovascular end points. CONCLUSIONS: The DD genotype of the ACE I/D polymorphism was an independent risk factor for renal but not cardiovascular end points in Chinese patients with type 2 diabetes.

Aged↗

PubMed1997

Pregnancy-associated deaths in Finland 1987-1994--definition problems and benefits of record linkage.

BACKGROUND: Our aim was to study the impact of record linkage and different classification principles on maternal mortality rate. METHODS: The death certificates of all fertile-aged women who died in 1987-94 in Finland (n = 9,192) were linked to the Birth, Abortion, and Hospital Discharge Registers (n = 513,472 births, 93,807 induced abortions, and 71,701 other ended pregnancies) to identify the women who had been pregnant during their last year of life. All deaths that occurred up to 1 year after the end of pregnancy were classified according to their connection to pregnancy. RESULTS: In total, 281 qualifying deaths were found. Only in 22% of the death certificates was the pregnancy or its end mentioned. The mortality rate was 41 per 100,000 registered ended pregnancies (27 for births, 48 for miscarriages or ectopic pregnancies, and 101 for abortions). The maternal mortality rate depended greatly on which of these 281 cases were defined as maternal deaths. The early maternal mortality rate varied between 5.6 and 6.8 per 100,000 live births, and the late maternal mortality rate between 0.6 and 2.5 depending on the definition used. The classification of other than direct maternal deaths was ambiguous, especially in case of late cancers, cardio- and cerebrovascular diseases, and early suicides. The official Finnish figure for early maternal mortality (6.0/100,000 live births) seems to be a good estimate, although only 65% of individual deaths were unambiguously classified. CONCLUSIONS: Register linkage is necessary to identify late maternal deaths and pregnancy-associated deaths. The current official classification of maternal deaths as indirect, direct and fortuitous is arbitrary and allows much variation in defining a maternal death.

Adult↗

PubMed1995

Medicolegal investigative system and sudden death in Scandinavia.

The Nordic region consists of Denmark, with the autonomous territories of the Faeroes and Greenland, Finland, with the autonomous Aland Islands, Iceland, Norway, and Sweden. However, this review deals only with the situation in Norway, Denmark, Sweden and Finland. In these four countries only a physician can confirm that a person is dead and practically any physician can certify a death due to natural causes if he knows the cause of death. A clinical autopsy can be performed to confirm the diagnosis with the permission of the relatives. The regulations concerning the reporting and investigation of sudden unexpected and non-natural deaths are very similar in all Nordic countries. In general those deaths, which are criminal, suspicious, accidental, suicidal, sudden and unexpected, unexplained or in any way not due to natural causes, cannot be certified by a doctor and must be reported to the police for medico-legal investigation. Forensic Medicine exists as a medical specialty at present only in Finland and Sweden. The total autopsy rates vary from country to country, with the lowest autopsy rate in Norway-10.6% of all deaths, followed by Denmark-16%, Sweden-22% and Finland-31.1%. Despite the apparent similarities in legislation regarding those deaths which should be referred for medicolegal examination, the practices differ so much in the different countries that it is, in fact, not possible to make many valid comparisons. The number of Group XVI-cases (symptoms and ill-defined causes of death) of the International Classification of Diseases (ICD) in the mortality statistics of each Nordic country seems to be inversely correlated to the autopsy rate. This gives some indication of the efficacy of the certification of death in a given country. Finland, having the highest autopsy rate, has the lowest number of ill-defined causes of death. The declining autopsy rate in all Nordic countries seems to be in line with the international trend. If this tendency continues, it will, without doubt, have a negative impact on the reliability of mortality statistics in general and, in the individual case, increase the possibility of incorrect classification of the mode of death. In the worst instance this might result in failure to detect homicide.

Autopsy↗

PubMedDate not supplied

Differences in morbidity measures and risk factor identification using multiple data sources: the case of coronary heart disease.

The NHANES I Epidemiologic Followup Study contains several sources of information that can be used to define case status. Incidence rates and relative risks associated with selected, documented risk factors for heart disease were estimated using nine different case definitions. Despite wide variation in the estimates of incidence, the characteristics of the cases were remarkably similar as were the risks associated with heart disease incidence. The main difference occurred when cases were defined on the basis of death certificate information. Cases defined this way are more severe and models based on this definition result in relative risks of greater magnitude.

Aged↗

PubMed1995

Dignified death: a German perspective.

After discussing some defining questions concerning dignified death, active and passive euthanasia, assisted suicide and the criteria for free will and informed consent, the juridical situation in Germany is reported. Passive euthanasia according to the patients' free will is accepted, assisted suicide, active euthanasia, and passive euthanasia without informed consent are not accepted. The ethical discussion on these topics in Germany reveals a spectrum of opinions. There is somewhat more emphasis on the cons than on the pros. Humanistic and economic arguments merge in the debate. The philosophy of consequentialistic utilitarianism is heavily criticized by many authors who warn that respect even for the unproductive life must not fade. After some remarks on empirical studies on attitudes towards death and the history of attitudes towards euthanasia the conclusion lists the arguments, pros and cons, and gives a personal view.

Ethics, Medical↗

PubMed2005

CD4(+) cell count increase predicts clinical benefits in patients with advanced HIV disease and persistent viremia after 1 year of combination antiretroviral therapy.

The relationship between 12-month CD4(+) cell count response and clinical outcome (AIDS-defining event or death) in a subset of 228 patients with a human immunodeficiency virus load >400 copies/mL despite receiving combination antiretroviral therapy as part of a larger randomized trial was defined by use of Cox models. The 12-month CD4(+) cell count responses were divided into 5 categories, ranging from decrease or no change (29% of patients) to a > or =100-cell/mm(3) increase (27% of patients). There was a lower risk of clinical progression for each incremental increase in CD4(+) cell count response. A 25-cell/mm(3) increase in CD4(+) cell count was associated with a 21% reduction in the risk of an AIDS-defining event or death (P<.0001).

Antiretroviral Therapy, Highly Active↗

PubMed2006

Do prevailing societal models influence reports of near-death experiences?: a comparison of accounts reported before and after 1975.

Transcendental near-death experiences show some cross-cultural variation that suggests they may be influenced by societal beliefs. The prevailing Western model of near-death experiences was defined by Moody's description of the phenomenon in 1975. To explore the influence of this cultural model, we compared near-death experience accounts collected before and after 1975. We compared the frequency of 15 phenomenological features Moody defined as characteristic of near-death experiences in 24 accounts collected before 1975 and in 24 more recent accounts matched on relevant demographic and situational variables. Near-death experience accounts collected after 1975 differed from those collected earlier only in increased frequency of tunnel phenomena, which other research has suggested may not be integral to the experience, and not in any of the remaining 14 features defined by Moody as characteristic of near-death experiences. These data challenge the hypothesis that near-death experience accounts are substantially influenced by prevailing cultural models.

Adult↗

PubMed1995

CMV-DNA detection in parenchymatous organs in cases of SIDS.

A nested PCR approach has been developed especially for the detection of small amounts of cytomegalovirus (CMV) DNA in autopsy samples. Lung tissue and submandibular glands in 118 cases of infant death (92 SIDS cases, 13 natural deaths due to other defined causes and 13 unnatural deaths) were investigated by this technique and compared to the results obtained by other CMV detection methods (histology, immunohistochemistry, in situ hybridization and PCR). CMV-DNA could be detected in the lung tissue in 7 cases of SIDS using nested PCR. Compared to conventional PCR (3 positive cases in lung tissue) the nested approach always gave glear results and showed less additional bands. In all cases where CMV could be detected in the lungs, positive results were also obtained in the submandibular glands. The nested PCR method proved to be a more sensitive technique than the other detection methods including PCR and hot start, and even minimal amounts of target DNA could be detected in the presence of human and bacterial background DNA.

Autopsy↗

PubMed1997

Determinants of the autopsy decision: a statistical analysis.

Our goal was to use cross-sectional national mortality data to provide a multivariable statistical analysis of the factors that contribute to the decision of whether an autopsy will be performed. The identification of determinants of the autopsy is an important prerequisite for finding cost-effective alternatives for arresting or reversing the decline of autopsy rates in the circumstances in which the autopsy can continue to make a crucial contribution to clinical medicine and public health. The source of the data was 1986 National Center for Health Statistics (Washington, DC) mortality data tapes for Kentucky, Maryland, Minnesota, and Washington for the 1986 calendar year. Separate multiple logistic regressions were conducted on these data on a state-by-state basis, with a total of 139,063 individual mortality records as the unit of analysis. The dependent variable in all models was autopsy (yes/no). Odds ratios for selected explanatory variables were estimated for all four states, and the relative contribution of each explanatory variable was studied in a detailed analysis of one state. In general, the following independent variables had a statistically significant positive relationship with whether an autopsy will be performed: male sex; nonwhite ethnicity; death due to ill-defined or unknown cause; death due to accident, suicide, or homicide; presence of a nationally recognized medical center in the county of death; and death occurring in a standard metropolitan statistical area. In general, the following independent variables had a statistically significant negative relationship with whether an autopsy will be performed: older age at death; higher income level of the decedent; death in a nursing home; death at home; and residency in the county of death. The two most important variables influencing the autopsy decision were age at death (especially old age) and death due to accident, homicide, or suicide.

Adolescent↗

PubMed2005

Tumour necrosis factor-induced death of adult human oligodendrocytes is mediated by apoptosis inducing factor.

Tumour necrosis factor (TNF)-induced death of oligodendrocytes, the cell type targeted in multiple sclerosis, is mediated by TNF receptor p55 (TNFR-p55). The ligation of TNFR-p55 induces several signal transduction pathways; however, the precise mechanism involved in human oligodendrocyte (hOL) death is unknown. We defined that TNF-induced death of hOLs is non-caspase dependent, as evidenced by lack of generation of caspases 8, 1 and 3 active subunits; lack of cleavage of caspases 1 and 3 fluorogenic substrates; and lack of hOL death inhibition by the general caspase inhibitor, ZVAD.FMK. Electrophoresis of TNF-exposed hOL DNA revealed large-scale DNA fragmentation characteristic of apoptosis-inducing factor (AIF)-mediated cell death, and co-localization experiments showed that AIF translocation to the nucleus occurred upon exposure to TNF. AIF depletion by an antisense strategy prevented TNF-induced hOL death. These results indicate that TNF-induced death of hOLs is dependent on AIF, information of significance for the design strategies to protect hOLs during immune-mediated demyelination.

Adult↗

PubMed2006

Interactions of cytokines, S-Adenosylmethionine, and S-Adenosylhomocysteine in alcohol-induced liver disease and immune suppression.

Alcoholic liver disease (ALD) remains a leading cause of death in the USA. Defining mechanisms for liver cell death in ALD in order to develop potential new agents for therapeutic intervention is a major focus of the authors' work. Abnormal cytokine metabolism is a major feature of ALD, and a thorough understanding of both mechanisms and interactions of cytokine overproduction and sensitization are critical to developing a possible treatment for ALD. S-Adenosylmethionine has been used in a variety of animal studies and clinical trials and has been reported to improve biochemical parameters of liver function. Last, immunosuppression associated with chronic alcohol abuse is an important predisposing factor to opportunistic infections and cancer. It is the authors' working hypothesis that alcohol consumption leads to chronic activation of the immune system.

Animals↗

PubMed2005

Provincial mortality in South Africa, 2000--priority-setting for now and a benchmark for the future.

BACKGROUND: Cause-of-death statistics are an essential component of health information. Despite improvements, underregistration and misclassification of causes make it difficult to interpret the official death statistics. OBJECTIVE: To estimate consistent cause-specific death rates for the year 2000 and to identify the leading causes of death and premature mortality in the provinces. METHODS: Total number of deaths and population size were estimated using the Actuarial Society of South Africa ASSA2000 AIDS and demographic model. Cause-of-death profiles based on Statistics South Africa's 15% sample, adjusted for misclassification of deaths due to ill-defined causes and AIDS deaths due to indicator conditions, were applied to the total deaths by age and sex. Age-standardised rates and years of life lost were calculated using age weighting and discounting. RESULTS: Life expectancy in KwaZulu-Natal and Mpumalanga is about 10 years lower than that in the Western Cape, the province with the lowest mortality rate. HIV/AIDS is the leading cause of premature mortality for all provinces. Mortality due to pre-transitional causes, such as diarrhoea, is more pronounced in the poorer and more rural provinces. In contrast, non-communicable disease mortality is similar across all provinces, although the cause profiles differ. Injury mortality rates are particularly high in provinces with large metropolitan areas and in Mpumalanga. CONCLUSION: The quadruple burden experienced in all provinces requires a broad range of interventions, including improved access to health care; ensuring that basic needs such as those related to water and sanitation are met; disease and injury prevention; and promotion of a healthy lifestyle. High death rates as a result of HIV/AIDS highlight the urgent need to accelerate the implementation of the treatment and prevention plan. In addition, there is an urgent need to improve the cause-of-death data system to provide reliable cause-of-death statistics at health district level.

Adult↗

PubMed1987

Chorioamnionitis: its association with pregnancy outcome and microbial infection.

In a study of 33 cases of perinatal death, chorioamnionitis was observed in 57.6% compared with 5% of 20 control cases (p less than 0.001) and in 70.8% of cases with no morphologic cause compared with 22.2% of cases with a defined cause of death (p less than 0.01). Chorioamnionitis was significantly associated with previous gestations (p less than 0.01), prolonged rupture of the membranes (p less than 0.001), prematurity (20 to 27 weeks' gestation) (p less than 0.001), and low birth weight (less than or equal to 1000 gm) (p less than 0.001) but not with elevated maternal white blood cell count or pyrexia. Overall, in patients with chorioamnionitis, the perinatal death rate was higher (p less than 0.01); more stillbirths occurred compared with early neonatal deaths (p less than 0.05), and there was a higher incidence of deaths with no defined cause (p less than 0.01) compared with cases without chorioamnionitis. Ureaplasma urealyticum or pathogenic bacteria were isolated more frequently from villous tissue of placentas from cases with chorioamnionitis (p less than 0.01) but not Mycoplasma hominis, Chlamydia trachomatis, or viruses. Furthermore, there was a higher prevalence of both elevated fetal antibody titer to U. urealyticum (p less than 0.025) and fetal titer fourfold above maternal titers (p less than 0.05) in cases with chorioamnionitis. The antibody responses and presence of microorganisms suggest that chorioamnionitis is associated with intrauterine infection and an associated increase in perinatal morbidity and mortality.

Bacterial Infections↗

PubMed2006

DNA-binding independent cell death from a minimal proapoptotic region of E2F-1.

The ability to induce cell cycle progression while evading cell death is a defining characteristic of cancer. Deregulation of E2F is a common event in most human cancers. Paradoxically, this can lead to both cell cycle progression and apoptosis. Although the way in which E2F causes cell cycle progression is well characterized, the pathways by which E2F induces cell death are less well defined. Many of the known mechanisms through which E2F induces apoptosis occur through regulation of E2F target genes. However, mutants of E2F-1 that lack the transactivation domain are still able to induce cell death. To further investigate this activity, we refined a transactivation independent mutant to identify a minimal apoptotic domain. This revealed that only 75 amino acids from within the DNA-binding domain of E2F-1 is sufficient for cell death and that this activity is also present in the DNA-binding domains of E2F-2 and E2F-3. However, analysis of this domain from E2F-1 revealed it does not bind DNA and is consequently unable to transactivate, repress or de-repress E2F target genes. This provocative observation therefore defines a potential new mechanism of death from E2F and opens up new opportunities for inducing cell death in tumours for therapeutic gain.

Animals↗

PubMed2002

Cell death and mechanoprotection by filamin a in connective tissues after challenge by applied tensile forces.

Cells in mechanically challenged environments must cope with high amplitude forces to maintain cell viability and tissue homeostasis. Currently, force-induced cell death and the identity of mechanoprotective factors are not defined. We examined death in cultured periodontal fibroblasts, connective tissue cells that are exposed to heavy applied forces in vivo. Static tensile forces (0.48 piconewtons/microm2 cell area) were applied through magnetite beads coated with collagen or bovine serum albumin. There was a time-dependent increase of the percentage of propidium iodide-permeable cells in force-loaded cultures incubated with collagen but not bovine serum albumin beads, indicating a role for integrins. Cells exhibited reduced mitochondrial membrane potential, increased caspase-3 activation, nuclear condensation, terminal deoxynucleotidyl transferase nick end labeling staining, and detachment from the culture dish. The caspase-3 inhibitor acetyl-Asp-Glu-Val-Asp-aldehyde reduced detachment 3-fold. There was a rapid (<10-s) decrease in plasma membrane potential after force application, which, in filamin A-deficient melanoma cells, contributed to irreversible cell depolarization. In fibroblast cultures, cells with increased permeability to propidium iodide exhibited approximately 2-fold less filamin A content than impermeable cells. Fibroblasts transfected with antisense filamin A constructs or with filamin A constructs without an actin-binding domain exhibited 2-3-fold increased proportions of dead cells relative to controls. We conclude that high amplitude forces delivered through integrins can promote apoptosis in a proportion of cells and that filamin A confers mechanoprotection by preventing membrane depolarization.

Actins↗

PubMed2004

Medical and legal considerations of brain death.

Brain death was first defined in 1968, and since then laws on determining death have been implemented in all countries with active organ transplantation programs. As a prerequisite, the aetiology of brain death has to be known, and all reversible causes of coma have to be excluded. The regulations for the diagnosis of brain death are most commonly given by the national medical associations, and they vary between countries. Thus, the guidelines given in the medical textbooks are not universally applicable. The diagnosis is based on clinical examination, but confirmatory tests, such as angiography or EEG, are allowed on most occasions. Brain death is followed by cardiovascular and hormonal changes, which have implications in the management of a potential organ donor. Spinal reflexes are preserved, and motor and haemodynamic responses are frequently observed in brain dead patients.

Brain Death↗

PubMedDate not supplied

Randomized, double-blind trial comparing indinavir alone, zidovudine alone and indinavir plus zidovudine in antiretroviral therapy-naive HIV-infected individuals with CD4 cell counts between 50 and 250/mm3.

Treatment with indinavir has been shown to result in marked decreases in viral load and increases in CD4 cell counts in HIV-infected individuals. A randomized double-blind study to evaluate the efficacy of indinavir alone (800 mg q8h), zidovidine alone (200 mg q8h) or the combination was performed to evaluate progression to AIDS. 996 antiretroviral therapy-naive patients with CD4 cell counts of 50-250/mm3 were allocated to treatment. During the trial the protocol was amended to add lamivudine to the zidovudine-containing arms. The primary endpoint was time to development of an AIDS-defining illness or death. The study was terminated after a protocol-defined interim analysis demonstrated highly significant reductions in progression to a clinical event in the indinavir-containing arms, compared to the zidovudine arm (p<0. 0001). Over a median follow-up of 52 weeks (up to 99 weeks), percent reductions in hazards for the indinavir plus zidovudine and indinavir groups compared to the zidovudine group were 70% and 61%, respectively. Significant reductions in HIV RNA and increases in CD4 cell counts were also seen in the indinavir-containing groups compared to the zidovudine group. Improvement in both CD4 cell count and HIV RNA were associated with reduced risk of disease progression. All three regimens were generally well tolerated.

Adult↗

PubMed2004

Transcriptional signature of flavopiridol-induced tumor cell death.

Flavopiridol has been shown to inhibit the proliferation of a variety of human tumor cells and is currently undergoing clinical evaluation in cancer treatment. Although the antiproliferative effect of flavopiridol has been attributed to the inhibition of cyclin-dependent kinases 2 and 4, recent reports indicate that the mechanism responsible for the cell death induced by this agent is more complex. To provide insight into the molecular processes mediating flavopiridol-induced cytotoxicity and to investigate the availability of markers indicative of its activity, we have applied cDNA microarray technology. Gene expression profiles were determined for four human tumor cell lines (prostate carcinomas PC3 and DU145 and gliomas SF359 and U251) following exposure to selected concentrations of flavopiridol. Treatment of these cell lines with a concentration of flavopiridol sufficient to reduce survival to 10% resulted in the identification of a set of 209 genes, the expression of which were altered in each of the cell lines. This common set of 209 gene expression changes suggested that flavopiridol-induced cell death can be defined in terms of a specific transcriptome. The flavopiridol death transcriptome consisted primarily of down-regulated genes; however, there were also a significant number of genes with increased expression. Whereas causal relationships were not established, these data suggest molecular events/processes that may be associated with flavopiridol-induced tumor cell death. Moreover, the identification of a set of gene expression changes in four human tumor cell lines suggests that such a transcriptome may be applicable to investigations of flavopiridol pharmacodynamics.

Antineoplastic Agents↗